Requested is a SDAC (Level II) to study the molecular genetics of schizophrenia. Schizophrenia is a chronic psychiatric disorder of unknown etiology. Population genetic studies have suggested an important role for genetic factors in its pathogenesis; the nature of these factors remains unknown. Genetic linkage analysis has emerged as a powerful technique for initially providing the chromosomal location of major genes and ultimately identifying the pathogenic proteins underlying a variety of disorders. Given its success in uncovering the bases of rare, albeit simple Mendelian disorders, linkage analysis is now being directed toward more common, but complex disorders like schizophrenia. Columbia University is one of three collaborating sites, nationwide, involved in the evaluation of 200 pedigrees segregating schizophrenia. The studies described in this application will facilitate the subsequent linkage analysis of these pedigrees. In linkage analysis, one evaluates the likelihood of genetic linkage between disease phenotype and marker loci. The inherited phenotype in schizophrenia is unknown; a multivariate approach to defining such a phenotype is proposed. Marker loci fall into 3 types: anonymous markers (highly polymorphic DNA sequences from throughout the genome), favored locus markers (markers derived from specific chromosomal regions associated with the disease, usually through cytogenetic anomalies), and candidate gene markers (markers related to specific genes that have been implicated in disease pathogenesis). Computer simulation will be used to develop an efficient strategy for systematically searching the genome with anonymous markers. A putative favored locus for schizophrenia on chromosome 5q will be evaluated by examining systematically ascertained dysmorphic patients with schizophrenia for microdeletions and inversions in this region. This study will serve as a prototype for similar studies of other favored regions that may be identified. Linkage analysis with the 5 known dopamine receptor genes as (hypothesis-dependent) candidate genes will be undertaken. Analysis with hypothesis-independent genes coding for schizophrenia-relevant brain antigens will be performed. Other novel candidate genes, derived from schizophrenia-relevant mRNAs will also be examined for linkage in these pedigrees. These studies should not only aid in the detection of linkage, but may allow for finer specification of the obligate chromosomal region containing a disease gene. Candidate markers which are identified may provide clues to disease pathogenesis. During the tenure of this award, the Principal Investigator will develop greater expertise in the use of computer modeling in genetic epidemiology and in molecular biological and molecular genetic techniques, and gain additional knowledge of phenotype genotype interactions in schizophrenia.